TAILIEUCHUNG - Báo cáo khoa học: Active-site-specific chaperone therapy for Fabry disease Yin and Yang of enzyme inhibitors

Protein misfolding is recognized as an important pathophysiological cause of protein deficiency in many genetic disorders. Inherited mutations can disrupt native protein folding, thereby producing proteins with misfolded conformations. | MINIREVIEW Active-site-specific chaperone therapy for Fabry disease Yin and Yang of enzyme inhibitors Jian-Qiang Fan1 and Satoshi Ishii2 1 Department of Human Genetics Mount Sinai Schoolof Medicine New York NY USA 2 Department of Agriculturaland Life Sciences Obihiro University of Agriculture and Veterinary Medicine Japan Keywords active-site-specific chaperone 1-deoxygalactonojirimycin endoplasmic reticulum associated degradation Fabry disease a-galactosidase A pharmacological chaperone protein misfolding Correspondence . Fan Department of Human Genetics Mount Sinai School of Medicine Fifth Avenue at 100th Street New York NY 10029 USA E-mail Declaration of interest . Fan and S. Ishii are coinventors of patents related to the ASSC technology which is now licensed to Amicus Therapeutics Inc. Cranbury NJ USA and declare competing financialinterests Received 8 June 2007 accepted 13 August 2007 doi Protein misfolding is recognized as an important pathophysiological cause of protein deficiency in many genetic disorders. Inherited mutations can disrupt native protein folding thereby producing proteins with misfolded conformations. These misfolded proteins are consequently retained and degraded by endoplasmic reticulum-associated degradation although they would otherwise be catalytically fully or partially active. Active-site directed competitive inhibitors are often effective active-site-specific chaperones when they are used at subinhibitory concentrations. Active-site-specific chaperones act as a folding template in the endoplasmic reticulum to facilitate folding of mutant proteins thereby accelerating their smooth escape from the endoplasmic reticulum-associated degradation to maintain a higher level of residual enzyme activity. In Fabry disease degradation of mutant lysosomal a-galactosidase A caused by a large set of missense mutations was demonstrated to occur within the endoplasmic .

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